Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)

Abstract

Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding and motivated behaviors. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca²⁺-activated K⁺ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K⁺ (GIRK) channels in POMC neurons and GABA_B receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABA_B receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24 h following steroid administration in vivo, the GABA_B/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α₁-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K⁺ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.

Introduction

It is becoming increasingly evident that the gonadal steroid hormone estrogen imparts a multifaceted influence over synaptic transmission in the mammalian central nervous system. Not only can estrogen alter synaptic responses via genomic mechanisms, but there is a wealth of information that indicates the steroid can also modulate cell-to-cell communication much more rapidly (for review see [1]. These synaptic alterations are brought about via changes in the cellular responsiveness to the activation of various receptor systems (both G protein-coupled and ionotropic) to their respective first messengers. For example, estrogen can modulate the cellular responsiveness to ionophoric glutamate (both N-methyl-d-aspartate (NMDA) and non-NMDA) receptor activation [2], [3]. In addition, it can alter the linkage of G protein-coupled receptor systems such as opioid (both μ and κ), γ-aminobutyric acid (GABA)_B and dopamine D2 receptors to their respective effector systems [4], [5], [6], [7], [8]. Furthermore, it now appears that the steroid can function as a first messenger by activating an estrogen receptor that couples directly to K⁺ and Ca²⁺ channels by way of a pertussis toxin-sensitive G protein [9], [10]. These fundamentally distinct signaling pathways give rise to a coordinated regulation by estrogen of complex physiological processes such as reproduction, stress responses, feeding and cognition. We will focus on the estrogenic modulation of K⁺ channel activity in hypothalamic neurons involved in many of these physiological processes.